The present invention relates to novel galenic forms of verapamil, their manufacture and medicines containing said novel galenic forms.
Verapamil or 5-(3,4-dimethoxyphenylethyl)methyl-2-(3,4-dimethoxyphenyl)-2-isopropyl valeronitrile of formula I is known since more than 20 years and the synthesis thereof is described in Belgian Pat. No. 615,816 corresponding to U.S. Pat. No. 3,261,859, to Dengel. ##STR1##
Verapamil chlorhydrate is used in medicine in view of its outsetting properties as the calcium intracellular penetration antagonist. This characteristic makes from it an interesting medicine for the treatment of angor pectoris when the crisis or attack is bound to a coronary spasm and when undesirable effects of beta-adrenolytic products such as propranolol, timolol, atenolol and pindolol, are to be feared for. Said substance is also useful in the treatment of hypertension or too high blood pressure and of troubles of the cardiac rhythm.
It is known from the skilled men that the pharmacological action of verapamil is proportional to its plasmatic concentration (Br. J. Clin. Pharmac. (1981), 12, 397-400) and that the optimum therapeutic zone is comprised between 100 ng/ml and 400 ng/ml of plasma.
The major disadvantage of a treatment based upon verapamil is due to its very short plasmatic half-life period (2 to 4 hours), which requires several daily administrations spaced of 6 hours only. Such near administration times render the treatment very annoying or even impossible to be carried out, particularly by night. Moreover, after each administration of a galenic form of verapamil with immediate release, i.e. generally four times per day, a succession of fast increasing and decreasing plasmatic ratios are established. The organism and namely the targed-organ, more particularly the heart, are alternatively subjected to overdoses and to underdoses of medicine.
In order to palliate these drawbacks, a first galenic form with sustained-release of verapamil, called "Isoptine Retard.RTM." and presented as a tablet constituted of an hydrophilic matrix, was put onto the market. Although said sustained-release galenic form allows to eliminate concentration peaks, the bioavailability of verapamil from this galenic form is extremely low, such as will be told hereinafter, so that said form does not permit to achieve practically the plasmatic therapeutic ratios and, consequently, renders difficult the obtention of a satisfying clinical effect.